Eugenol enhancement of transdermal drug delivery

ABSTRACT

Disclosed herein are compositions and methods for enhancing the transdermal delivery of physiologically active agents across mammalian skin or membranes and which comprise a percutaneous transfer enhancing amount of eugenol and a drug.

BACKGROUND OF THE INVENTION

This invention relates to the transdermal delivery of physiologicallyactive agents and more particularly to the enhancement of the transferof such agents percutaneously by incorporation into the transdermaldelivery system of a small amount of eugenol.

The development of new or improved dosage forms and delivery means forphysiologically active agents has been and will continue to be thesubject of research for both existing and novel drugs. In too manyinstances a particular drug dosage provides for more drug than isactually required to produce an efficacious and safe therapeutic bloodlevel free from side effects. The reasons for such theoreticallyexcessive doses are many and include, inter alia, the mode ofadministration, the metabolism of the drug in the gastrointestinaltract, the absolute absorbtion (bioavailability) of the drugs and thesitus of absorption. In another aspect the use of sustained releasedosage forms and delivery means has increased to further both patientcompliance and convenience.

More recently, investigations respecting transdermal drug deliverysystems have increased resulting in a number of commercially availableproducts especially for the administration of nitroglycerine. Theselatter systems apparently provide the advantages inherent in sustaineddelivery dosage forms and avoid the problems of a drug's rapidmetabolism upon oral administration. At the same time less drug,although equally efficacious therapeutically to a greater amount orallyadministered, is ingested or absorbed by the patient. Nevertheless, thefeasibility, the success and potential of such transdermal systems haveheretofore been limited to drugs that are efficacious at lower doselevels and/or have relatively limited water solubility. The explanationfor such limitations arise from the formidable barrier provided by theexternal layer(s) of animal skin and membrane tissues and the limitedbody areas which are usefully available for application of suchtransdermal dosage forms.

Various efforts have been pursued to expand the availability oftransdermal delivery to more drugs and overcome the barrier presented byanimal skin and membrane. Most such efforts, at least those employingtransdermal drug delivery devices, have concentrated on increasing thediffusion of the drug from the device into and through theaforementioned barriers. Other efforts have been more specificallytargeted at improving the permeability characteristics or percutaneousabsorption capacity of the barrier itself. While some of these latterefforts have reportedly shown some success, the agents employedfrequently have caused undesirable systemic side effects as well astissue damage and irritation at the situs of application.

Agents reported to act as penetration enhancers for transdermal drugdelivery include dimethylsulfoxide, disclosed in U.S. Pat. No.3,551,554; combinations of sucrose fatty acid esters with a sulfoxide orphosphoric oxide, disclosed in U.S. Pat. Nos. 3,896,238; 3,952,099 and4,046,886; and the 1-substituted azacycloalkan-2-ones which are thesubject of U.S. Pat. Nos. 3,989,816; 4,316,893 and 4,405,616.

SUMMARY OF THE INVENTION

The present invention relates to compositions useful for the transdermaldelivery of physiologically active agents to mammals. More particularly,this invention relates to compositions and methods which enhance thepercutaneous transfer of topically applied, systemically active drugsand particularly such drugs which have aqueous solubility or which canbe made water soluble by the use of derivatives, or in composition,through selection of appropriate pH, buffers, solvents and excipients.Thus the composition of this invention comprises at least onesystemically active, water soluble or solubilizable drug, a percutaneoustransfer enhancing amount of eugenol and a pharmaceutically acceptablevehicle in which the eugenol is soluble.

The structure formula for eugenol is: ##STR1##

In a further aspect, the invention relates to a method for enhancing thetransfer of physiologically active agents into and through mammalianskin and membranes. The method comprises topically applying oradministering to substantially the same section of the mammalian skin ormembrane an effective amount of a systemically active, water soluble orsolubilizable drug, a percutaneous transfer enhancing amount of eugenoland a pharmaceutically acceptable vehicle.

Still a further embodiment of this invention resides in a unit dosageform for transdermal delivery of physiologically active agents tomammals. The dosage form comprises an effective amount of a systemicallyactive, water soluble or solubilizable drug comprised within at leastone drug reservoir means; a percutaneous transfer enhancing amount ofeugenol comprised within eugenol delivery means; eugenol solubilizingmeans and securing means for attaching the dosage form to a mammal.

DETAILED DESCRIPTION OF THE INVENTION

Eugenol can be obtained naturally from clove or other oils or preparedsynthetically. It has now been found that eugenol acts to enhance thepercutaneous transfer of systemically active drugs in mammal.

Thus, this invention provides a topical composition for the transdermaldelivery of physiologically active agents to mammals, said compositioncomprising an effective amount of a systemically active, water solubleor solubilizable drug, a percutaneous transfer enhancing amount ofeugenol and a pharmaceutically acceptable vehicle comprising at leastone pharmaceutically acceptable solvent or solubilizer for said eugenol.

In this invention the effective amount of drug will mean that amount ofdrug needed to produce a therapeutic dose following its transdermaladministration. That amount will vary, depending, among other factors,on the physiological effect desired, the frequency of administration,drug and intradermal metabolism, drug half-life and the amount ofeugenol and perhaps other percutaneous transfer enhancers employed inthe composition.

As stated, a percutaneous transfeer enhancing amount of eugenol iscomprised in the composition. This amount for most drugs, generallyranges from about 4 to about 16 percent by weight of the composition.

The composition of the invention will further include a pharmaceuticallyacceptable vehicle containing at least one pharmaceutically acceptablesolvent or solubilizer for said eugenol. The vehicle in preferredcompositions will also contain at least one pharmaceutically acceptablesolvent which is a solvent or solubilizer for the drug. The respectivesolvents or solubilizers for the drug and eugenol of this invention maybe the same or different. In either case it is preferable that thesolvents or solubilizers for each the drug and eugenol, in the amountsemployed, are at least partially soluble or miscible with each other.Most preferably, the solvents or solubilizers for each the drug and theeugenol will, in the amounts employed, be wholly soluble or misciblewith each other. Thhe pharmaceutically acceptable vehicle may alsocontain other pharmaceutically acceptable excipients useful forformulating topical pharmacuetical compositions including buffers,neutralizing agents, pH modifiers, viscosity building or controllingagents, gel forming agents, emulsifiers, surfactants, polymers and thelike.

Examples of solvents or solubilizers which may comprise thepharmaceutically acceptable vehicle of this invention include one ormore of materials such as glycerin, propylene glycol, isopropanol,ethanol, a variety of polyethylene glycols, block copolymers of ethyleneglycol and propylene glycol, acetylated monoglycerides, lanolin, mineraloil, water, aqueous buffers and the like.

The composition of this invention for application to mammalian skin ormembrane may take various forms including creams, lotions, gels,ointments, suppositories, sprays, aerosols and the like.

In another embodiment, the invention includes a method for treatingmammals in need of treatment with systemically active agents by thetransdermal administration of said agents sequentially or in combinationwith a percutaneous transfer enhancing amount of eugenol. The method iseffected by topically administering to substantially the same section ofmammalian skin or membrane an effective amount of a systemically active,water soluble or solubilizable drug, a percutaneous transfer enhancingamount of eugenol and a pharmaceutically acceptable vehicle. Thus, themethod of the invention may also be employed as referred to hereinabovein the Summary of the Invention as a method for enhancing the transferof physiologically active agents through mammalian skin and membranes.In either event the method may be realized through administration of thecomposition of the invention, a unit transdermal dosage form comprisingthe composition of the invention, or through sequential administrationof the percutaneous transfer agent and drug of this invention via directapplication to said mammal or via the unit transdermal dosage form ofthis invention comprising the same or different means for delivery ofeach of said percutaneous transfer agent and said drug.

The unit dosage form of this invention as hereinbefore describedcomprises an effective amount of a systemically active water soluble orsolubilizable drug comprised within at least one drug reservoir means.Said drug reservoir means may take various forms such as pads or spongesimpregnated with drug, a polymeric matrix containing the drug orcomposition of the drug, a gel formulation (or other formulation havingsome structural integrity) of the drug, a composition or solution of thedrug within a walled container permeable to the drug and available tothe skin or membrane of the mammal, a multiplicity of distinctmicroreservoir compartments containing the drug or drug compositionwithin or homogenously throughout each microreservoir, layers ofreservoirs and multiple variants of any of these enumerated and otherdrug reservoir presentations.

The unit dosage form, as with the other embodiments of this invention,further comprises a percutaneous transfer enhancing amount of eugenol.In the unit dosage form, the eugenol will be comprised within eugenoldelivery means which means can be selected from any of the describeddrug reservoir means, distinct eugenol reservoir means and integraleugenol reservoir means. Integral eugenol reservoir means is defined toinclude the provision of the eugenol together with the securing means,as for example in an adhesive layer.

Eugenol solubilizing means and securing means for attaching ormaintaining contact of the dosage form to a mammal are also comprised bythe unit dosage form of the invention. The eugenol solubilizing meanscomprise a pharmaceutically acceptable vehicle in which the eugenol issoluble or solubilizable and which further is also either a solvent forthe drug or is miscible with the drug or drug composition. Thus theeugenol solubilizing means may be formulated with any of the eugenol,the drug and/or in a distinct reservoir or depot within the unit dosageof the invention, so long as the eugenol is soluble or made solubletherein and the drug or drug composition is soluble or miscibletherewith prior to transfer through the skin or membrane of the mammal.The securing means will be selected from adhesives, belts such as thosewith "velcro" fittings, elastic bands or such other devices which arecapable of securely attaching the unit dosage to the mammalian subject.

The invention is further illustrated by the following examples.

The examples given below are the results of in vitro diffusion cellexperiments performed on freshly excised nude mouse skin. A piece offreshly excised nude mouse skin was mounted across the 0.79 cm² openingof a diffusion cell. Between 10 and 20 mg of test formulation wasimpregnated into 0.79 cm² disks of non-woven rayon fabric and theseimpregnated circles were applied to the epidermal side of the skin. Thedermal side of the skin was in contact with pH 7.4 buffer solutionmaintained at 32° C. for 24 hours. The receiving fluid was periodicallysampled and assayed for drug content. For albuterol formulations, theanalyses were conducted by HPLC. In the case of hydrocortisone, theformulations were radiolabeled with H³ -hydrocortisone. Analyses ofthese formulations were based upon the radioactivity in the receivingfluid as determined by liquid scintillation counting. Formulations foreach drug were prepared in one solvent system and varying amounts ofeugenol, were added systemically. The total percent of drug diffusedthrough the skin was determined and this value was compared to anunenhanced formulation of the drug in the solvent system. The resultsare presented in the following examples and show conclusively thateugenol, facilitates percutaneous diffusion of drugs.

EXAMPLE I Percutaneous Diffusion of Albuterol through Nude Mouse Skinfrom Eugenol Enhanced Formulations

    ______________________________________                                         Formu-                      Total Percent                                    lation   Formulation (w/w %) Drug Diffused                                    #       Albuterol Solvent** Eugenol                                                                              in 24 Hours                                ______________________________________                                        A1      5         95         0     33.9                                       A8      5         90         5     28.3                                       A9      5         85        10     47.1                                        A10    5         80        62     77.0                                       ______________________________________                                         **Solvent = 33% N--methy2-pyrrolidone 67% Diethylene glycol monoethyl         ether                                                                    

EXAMPLE II Percutaneous Diffusion of Hydrocortisone through Nude MouseSkin from Eugenol Enhanced Formulations.

    ______________________________________                                               Formulation (w/w %)                                                                              Total Percent                                       Formulation                                                                            Hydro-                    Drug Diffused                              #        cortisone                                                                              Solvent** Eugenol                                                                              in 24 Hours                                ______________________________________                                        H1       5        95         0     2.9                                        H10      5        94         1     1.3                                        H11      5        90         5     5.3                                        H12      5        85        10     15.2                                       H13      5        80        15     11.3                                       H14      5        75        20     6.0                                        ______________________________________                                         **Solvent = 3,6% N--methyl2-pyrrolidone 96.4% Propylene glycol           

What is claimed is:
 1. A composition for the transdermal delivery ofphysiologically active agents to mammals by topical administrationcomprising an effective amount of a systemically active, water solubleor solubilizing drug, a percutaneous transfer enhancing amount ofeugenol and a pharmaceutically acceptable vehicle comprising at leastone pharmaceutically acceptable solvent or solubilizer for said eugenol,said enhancing amount of eugenol comprising by weight about 5% to about16% of the composition.
 2. The composition of claim 1 in which thepharmaceutically acceptable vehicle further comprises at least onepharmaceutically acceptable solvent for the drug.
 3. The composition ofclaim 2 in which the solvents for each of the drug and the eugenol arein the amounts employed, at least partially miscible with each other. 4.A method for enhancing the transfer of physiologically active agentsthrough mammalian skin and membranes comprising topically administeringto substantially the same section of mammalian skin or membrane aneffective amount of a systemically active, water soluble orsolubilizable drug, a percutaneous transfer enhancing amount of eugenoland a pharmaceutically acceptable vehicle.
 5. The method of claim 4wherein said drug and said percutaneous transfer amount of eugenol aresupplied to said mammal sequentially.
 6. The method of claim 4 whereinsaid drug and said percutaneous transfer amount of eugenol are suppliedto said mammal simultaneously.
 7. The method of claim 4 wherein theeugenol is soluble in said vehicle.
 8. The method of claim 4 wherein theeugenol is soluble in said vehicle and the drug is at least partiallysoluble in said vehicle.
 9. The method of claim 4 wherein each of thedrug and the eugenol are comprised in separate solubilizing compositionstherefor and each of said compositions are substantially miscible withthe other of said compositions and wherein at least one of saidcompositions contains said pharmaceutically acceptable vehicle.
 10. Atopical composition for the transdermal delivery of physiologicallyactive agents to mammals comprising an effective amount of asystemically active, water soluble or solubilizable drug selected fromthe group consisting of albuterol and hydrocortisone, a percutaneoustransfer enhancing amount of eugenol and a pharmaceutically acceptablevehicle comprising at least one pharmaceutically acceptable solvent orsolubilizer for said eugenol, said enhancing amount of eugenolcomprising by weight about 5% to about 16% of the composition.
 11. Amethod for enhancing the transfer of physiologically active agentsthrough mammalian skin and membranes comprising topically administeringto substantially the same section of mammalian skin or membrane aneffective amount of a systemically active, water soluble orsolubilizable drug selected from the group consisting of albuterol andhydrocortisone, a percutaneous transfer enhancing amount of eugenol anda pharmaceutically acceptable vehicle.